Anesthetic tannate



Patented UNITED TES- PATENT 1 OFFICE i I 2,100,054 I 'ANESTHETIC TANNATEI opkinsong'andAlexander V. Tolstoouhov, v New York',lN. Y., assignorsto Ostro Research Laboratoriealna, New York; N. Y., a corporation ofNewJersey' 1- p No .DrawingJlApplicationOctober 27; 1933, i a .N0 69 i 4Claims. (Cl. 167-52) 7 p t This invention relatestonew compound and 9[In casesof painful burns, ulcers,' hemorrhoids,

compositions useful in the treatment 'o't scalds, etc; it is desirabletoadd anesthetic action to the burns,- denuded surfacesandotherpainfullsions astringent and Jantiseptic properties of tannic of theskin or mucous membranes, and; to the acid. This can'be accomplished bycombining j Process ofproducingthe'mo tannic. acldand local anesthetics,or by making Picric acid has been in .useior a long time'as saltsthereof. that have all-thesedesirable propera disinfectant 'andproteinprecipitant in the ties- Tannates of. local anesthetics generally are qtreatment of burnsflusually in the form of a fairly insoluble fat the pHor body fluids. This H water solution. It 'has some-anestheticproperproperty increases the length of action of I 101 gtieswhich are-ofcourse of greatwbenefit in the anesthetics and decreases their generaltoxicity, 10 treatment of burnsmI-Iowever, it has-several so'that. theyare safe for use on large areas; drawbacks, the most important .of whichis a The salts of anesthetics and 'tannic acid are, relatively highgeneral toxicity, especially when soluble in acid media at pH of about3.0-4.0. The p used on large areas. It also produces some local pH atwhich tannates of difierent anesthetics are l5 irritation to the tissuecells due to the fact that soluble varies widely. F r t e a m t v y i itis a fairly strong acid. Furthermore, it proof both the tannic acid andanesthetics th reduces an objectionablecyellow colorto the skin actionof the solutions or ointments containing which is difii'cult to remove.j them should be-just sufliclent to prevent the Local anesthetics in anoily base or carrier formation O vy ip tate- This a be have been usedfor some time in the treatment of obtained either by di a n te excessof. ,burns principally" for the purpose of relieving t c acid to t e S uy ddi g an acid pain, and ithas beenproposed heretofore to com- Salt O Pph i 0 other Weak ac such bine these two forms of 'treatment by the useof 5 citric acid, tartaricfblfphthalic d; i the picrates of certainlocal anesthetics; (U.' S. Tamlates of a e s can 'bQJJSOIatGd' l1,596,259 when the pH of the solutions areabovecertain Now we havediscovered that the tannates of fi u U u y when o u ion jl drdcocertain'local anesthetics'exhibitanumberof prop- Tides of 9 l St fl S"a d fi m c d'ar erties which render. them vastly superior to the i dthepH t l ;s ,1 \a ,i q1 w o ive t picrates in the treatment of burns orother painful cipi a o Of S h n hat 5.. I lesions. We have alsodiscovered asimple method Th m y P9 1 XP ,1 y Su whereby these tannates,whicliheretofore have 3V' P t,"D y b p dnot been known, can be preparedin a sufiiciently Tannat'es'bflocal es h may b P ep ed pure state toenable them to be used with safety. in 3 53 h Fhfp in i Tannic acid hasheretofore been'used chiefly as i y'mixingan alcohol solutionlof a localanesthetic an astringent for mucous membranes of the; e r q y base andasolution of mouth and intestinal tract and asan astringent 'm' acid; o n-a aq s ut n or and disinfectant in the preparation of the skin aanesthetic d hlo e anda queous of patients or hands of surgeons forurgia] 0p solution Of tannic acid; Other SC JIVGDJJS(Liitl'l. alsoerations. It has also been usedfor the treatbe U t 3 bh W -I T isolate40 ment of burns with good results; i the tannates .in y f r ,it pr a 2,use 40 Tannlc .acid has a .very low general'toxlcity. the aqueoussolu-tio adjust the pH in'each It is completely oxidized in the body,whether particular case, 'o asto-givethe maximum'pretaken by mouth orintravenously. This low cipitation of the ztannate' consistent withpurity fgeneral toxicity of tannic acid gives it a very of the.product.iThepligl is adjusted by adding 3 important advantage in comparison withplcrie an alkali, suchas sodiumfhydroxide, for example. 45 acid. Picricacid has the disadvantage that it The. precipitated tann'ate' mayberemoved by is sooner or later absorbed in the body and causesfilteringand is then ied. poisoning. This disadvantage is not present,Incarrying out his invention it has. been 1 with tannic acid as itforms protein. tannates found that tannates that are produced by causingwhich act as a protection. These tann'ate's'hav'e '-tannic acid to reactwith local anestheticsthatno poisonous propertiea}Tannic acid has alsohave basic properties are very efiective. We

. bactericidal properties. The "combination of .have. also found thattannates produced by causastringentand antiseptic properties togetherwith ing tannic acid to react with local anesthetics negligible toxicitymake tannic acid very useful that have basic properties dueto thefactthat' ootforthehumanbeingh1.1 I t a they contain an aminov groupor-a, substituted 5 amine are particularly useful in treating burns andother skin lesions. More particularly, local anesthetics that have basicproperties and have an aromatic nucleus, such as a naphthalene nucleusand others, can be used to form the tannate when reacted with tannicacid thus producing products veryuseful for the purposes of thisinvention. i v e The tannates of anesthetics prepared in accordance withthis invention can be incorporated into ointments, suppositories,pastes, etc. We

The precipitate is a brownish powder that is very diflicultly soluble inH2O, alcohol, and weak alkalies, but is soluble in dilute acids. Itsmelting point is 107-109" C.

The smallest visible precipitation of salt starts from N/ solutions ofthe hydrochloride of this anesthetic and free tannic acid at about pH4.38. Maximum precipitation takes place at about pH 7.08.

Example 3.Preparation of cz-blltYlOXYCiilchoninic aciddiethyl-ethylenediamide tannate:

prefer to use 1 to 5% by weight of the tannate in such vehiclesdepending on the strength of the particular local anesthetic that isused in making the tannate. i

- The following are given for illustrative purposes as specific examplesfor preparing the tannates of some local anesthetics, but it is to beunderstood that the invention is not restricted to these examples. r

Example 1.Preparation of l-ethoxy-i-(betadiethyl-amino-ethyl)-naphthalene tannate:

0 CIH Dissolve 1.5 gm. of tannic acid '(2 mols) in 100.0 cc. of H20 and0.9 gm. of 1-ethoxy-4-(beta-diethyl-amino-ethyl) -*naphthalenehydrochloride (1 mol.) in 25.0 cc. of H20. Mix the solutions and add25.0 cc. of N/10 NaOH to bring the pH of solution to 4.6. Filter theprecipitate that is formed, wash with H20 and dry in vacuo. As analternative, powdered tannic acid and hydrochlorides of anesthetics canbe dissolved together and-N/lO NaOH can be added to the mixtureafterwards. The yield is 92% of the theoretical yield. I

The precipitate or tannate is a light, creamy powder that is diflicultlysoluble in H2O, alcohol, and weak alkalies and is soluble in diluteacids. The melting point is -117 C. If the pH of the solution from whichthe precipitate is formed by adding the alkalies is above 4.6 theprecipitate turns purplish brown soon after it is formed.

The smallest visible precipitation of salt starts from N/100 solutionsof the anesthetic hydrochloride and free tannic acid at about ,pH 3.53.Maximum precipitation'of the salt takes place at about pH 4.55.

Example 2.-Preparation of diethyl-aminoethyl ester of p-amino benzoicacid tannate or Dissolve 1.5 gm. of tannic acid 2 mols) and 0.87 gm. ofprocaine hydrochloride (1 mol.) in 100 cc. of H20, add 20.0 cc. of N 10NaOH to'bring the pH of the solution to 6.0. Filter the precipitatewhich forms, wash a few times with H20 and dry in vacuo.

co n,

This tannate can be prepared in a similar way, i. e., by dissolving 2mols of a-butyloxycinchoninic acid diethyl-ethylenediamide hydrochlorideand 1 mol. of tannic acid in 100 cc. of water and adding NaOH. The pH ofthe solution should not be above 5.0. At higher pH the yields arehigher, but the salt is not stable. The salt obtained at thishigher'pI-I turns to a dark brown color.

This tannate is a brown powder. It is *difiicultly soluble in water,alcohol, and weak alkalies, and it is soluble in weak acids. Its meltingpoint is 9496 C.

The smallest visible precipitate of salt starts from N/ 100 solutions ofthe hydrochloride of this anesthetic and free tannic acid at about pH3.64. Maximum precipitation takes place at about pH Example4.Preparation of the tannate of methyl ethyl dimethylamino-methylcarbinol benzoate (stovaine). V

1 C O O-(f-CHaNGIHzOaHO O C (OIl)2.Caii2.O.0 C.CcH2(OH):

Dissolve 1.5 .gm. of tannic acid (2 mols) and. 0 gm. of stovainehydrochloride (1 mol.) mice of water. To precipitate the tannate add NNaOH solutions of the anesthetic hydrochloride and free tannic acid atabout pH-4.'69. Maximum precipitation of this salt takes place at aboutpH 5.22. The tannate melts at CHIC V n-O-omm Dissolve 1.5 gr. of tannicacidj(2 mols) plus 0.69

. gms of ethenyl-p diethoxydiphenylamidine hydrochloride' (1 mol.) in100 cc. 01' water. To precipitate the tannate add N' NaOl-I l .to bringthe pH to 4.98. Filter the precipitate that is formed, wash with watervacuo. a The tannate is a light creamy powder that is very poorlysoluble in water, alcohol, and weak alkalies, but is soluble in diluteacids.

The smallest visible precipitation of the salt starts from solutions ofthe anesthetic hydrochloride and free tannic acid at about pH 4.20.Maximum precipitation of salt takes place at about pH 4.98.

and dry in The tannate melts at 1509-155 with decomposition.

For application to painful lesions, the tannates described above, andother similar tannates, can be dissolved in water that is slightly 1 jacidified; or theymay be incorporated into ointmay be incorporated in aareaseless cream.

ments by methods well-known in the art; or they We prefer to use about 1to 5% of the tannate in any of theabove bases or carriers. r

A particularly useful ointment for serious burns, scalds,'etc. can beprepared by mixing 2 parts by weight of 1-.ethoxy-4-(beta-diethyltannicacid may be added to the above if'desired.

amino-ethyll-naphthalene tannate, 90 parts white Vaseline and 10v partslanolin. 2 parts of A very satisfactory creainfor the treatment ofsunburn can be prepared by mixing one or two parts by weight ofl-ethoizy-4-(beta-diethylamino-ethyl) -naphthalene tannate with 20 partsof glycerol mono stearate and 80 parts of water at C. and allowing themixture to cool while stirring. This produces a cooling greaseless creamhaving a neutral reaction. Several parts of Vaseline, lanolin orpetrolatum may be added to the above if desired.

Occasionally, physicians, prefer in the treatment of large burns to usean aqueous solution and to leave the areas uncovered until the naturalformation of a protective covering. An excellent wash can be preparedfor this purpose by dissolving one part by weight of 1-ethoxy-4-(beta-diethyl amino-ethyl) -naphthalene tannate and two parts of tannicacid in 100 parts of water. An alternative method is to dissolve onepart of the hydrochloride of the local anesthetic and five parts oftannic acid in 200 parts of water. Part of the tannic acid isimmediately used to form' the tannate. The advantage of this secondmethod is ease of preparation. This solution can be applied to thedenuded area by 1 means of tampons or swabs.

a In addition to theadvantage which the tannates of local anestheticshave over the corresponding picrates in being non-toxic, colorless andnon-staining, there is another important advantage. Tannic acid isan'oxygen absorbent and therefore acts to prevent the decomposition ofthe readily oxidizable local anesthetics when exposed to air. On theother hand, picric acid does not prevent this oxidation. The tannates oflocal anesthetics have been found to be much more stable than thecorresponding picrates.

Examplesof other local anesthetics, the tannates of which are useful inthe treatment of burns, denuded areas and other painful lesions I are:

Cocaine Tropacocaine v Trimethyl-benzoxy-piperidine (eucaine)Benzoxy-dimethylamino-methyl dimethyl-amijno butane (alypine)p-Amino-benzoyl dimethyl-amino-methyl-butanol (tutocaine) .p Aminobenzoyl gamma amino propanol (butyn). We claim:

- 1. A composition for treating'skin lesions having therein a compoundin the list consisting of 1-ethoxy-4-(betadiethyl amino-ethyl)naphthalene tannate, diethyl-amino-ethyl ester of p-amino benzoic acidtannate, a-butylox'y cinchoninic acid diethyl-ethylenediamine tannate,methyl ethyl dimethylamino-methyl carbinol benzoate tannate,ethenyl-p-diethoxydiphenylamidine tannate, tropacooaine tannate,trimethyl-benzoxy-piperidine tannate, benzoxydimethyl-amino-methyldimethyl-amino butane tannate, p amino benzoyl dimethylaminomethyl-butanol tannate, and p-amino-benzoyldinormalbutylgamma-dinormal-butylamino propanol tannate.

